Abstract B042: The PIK3CA/AKT pathway drives therapy resistance in rhabdomyosarcoma

Abstract Olaparib and temozolomide (OT) combination therapy is in clinical trial evaluation for rhabdomyosarcoma (RMS). Unfortunately, OT resistance has been reported in other cancers. Using preclinical mouse xenograft experiments, we show that OT effectively suppresses RMS growth, yet over half of RMS tumors develop resistance associated with transcriptomic changes that occur in the absence of recurrent genomic mutation. To date, our mechanistic studies have uncovered that OT resistance is driven by the PIK3CA/AKT pathway which in turn regulates expression of ABC transporters that are well-known to efflux drugs from cells and lead to therapy resistance in RMS. PIK3CA inhibitor alpelisib re-sensitizes resistant cells to OT by suppressing expression of ABC transporters. The combination of OT + alpelisib also kills RMS cells which are resistant to standard-of-care combination chemotherapy [vincristine, actinomycin D, and cyclophosphamide (VAC)] and was effective in preclinical xenograft mouse models at curbing tumor growth. We also observed that cells can transit from therapy resistant to sensitive states after long-term, serial passaging in the absence of drug in most therapy-resistant RMS cell models, which indicates the therapy-resistance may be commonly regulated by non-genetic mechanisms. Our work defines a common resistance pathway in RMS and has credentialed PIK3CA/AKT inhibition as a preclinical strategy to kill therapy resistant RMS. Citation Format: Yueyang Wang, Qiqi Yang, Luis A. Corchete Sanchez, Sabateeshan Mathavarajah, Yun Wei, Chuan Yan, Stephanie Strom, David Langenau. The PIK3CA/AKT pathway drives therapy resistance in rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_2):Abstract nr B042.